The goal of this new investigator research grant application is to conduct analyses exploring the interplay of genetic and environmental risk factors in the development of adolescent alcohol use, smoking, and related behaviors. Although it is widely accepted that genetic and environmental influences are both critical to the development of human behavior, most studies have explored these influences in parallel. A more complete understanding of the development of behavior necessitates direct study of how genetic and environmental influences interact to impact behavioral outcome. The incorporation of specific environmental measures into genetically informative designs and the development of more sophisticated mathematical models provides a powerful design to explore the effects of the environment and to test complex gene-environment interactions in ways not previously possible. Adolescent substance use provides a particularly relevant phenotype with which to study genetic and environmental interplay because multiple predictors, ranging from genes to familial, peer, school, and community influences, are known to be important. Secondary analyses of rich, existent twin datasets are proposed to study how environmental conditions act and interact with genetic predispositions in the development of patterns of adolescent substance use. FinnTwin12 (FT12) is a population-based twin study of five consecutive birth cohorts of Finnish twins, studied at ages 12, 14, and 17, and assessed with self-report questionnaire and interview, parental and teacher reports, and in-school peer assessments, providing comprehensive information on alcohol use and related behaviors, as well as information on the twin's home environment, peers, and relevant aspects of the school and community. Data from The Missouri Twin Studies, which have a comparable study design, with similar assessments of both substance use and related environments across adolescence, will be analyzed to test the generalizability of gene-environment interplay effects detected in the FT12 sample. These analyses have the potential to significantly enhance our understanding of the impact of environmental influences across adolescence and how the environment acts and interacts with genetic predispositions to impact behavioral outcome.